7-fluoro-prostacyclin analogs

ABSTRACT

The prostacyclins 7-fluoro-6,9-epoxy-16-substituted-15-hydroxyprost-[4 or 5,13]-dienoic acids and esters useful as anti-secretory agents, blood pressure lowering agents, anti-ulcerogenic agents, anti-hypertensive agents, bronchodilation agents and for combating gastro-hyperacidity and as anti-blood platelet aggregating agents.

CROSS REFERENCE TO RELATION APPLICATION

This is a division of application Ser. No. 414,765 filed Sept. 7, 1982,U.S. Pat. No. 4,558,142 which was allowed on Aug. 9, 1985, which is acontinuation-in-part of Ser. No. 337,791 filed Jan. 7, 1982 nowabandoned, which is a continuation-in-part of Ser. No. 242,818, filedMar. 11, 1981, now abandoned.

SUMMARY OF THE INVENTION

In accordance with this invention, compound of the formula ##STR1##wherein R is hydrogen or lower alkyl; R₁ is hydrogen, hydroxy or methyl;or R₂ is hydrogen, methyl or fluoro; and R₂ ' is fluoro, hydrogen,trifluoromethyl or methyl; and with the proviso that when R₂ ' istrifluoromethyl, R₂ is hydrogen or methyl

and salts thereof as well as optical antipodes and racemates thereof areuseful as antisecretory agents, anti-hypertensives, anti-ulcerogenicagents, blood pressure lowering agents and for combatinggastro-hyperacidity and for anti-blood platelet aggregating agents.

The compounds of formulas I-A and I-B are prepared from compounds of theformula: ##STR2## wherein R₁, R₂ and R₂ ' are as above or opticalantipodes or racemates thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this application, the term "lower alkyl" includesboth straight chain and branched chain alkyl groups having from 1 to 7carbon atoms such as methyl and ethyl. As also used herein, the term"lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbonatoms such as formic acid and acetic acid. As further used herein, theterm "halogen" or "halo", unless otherwise stated, comprehends fluorine,chlorine, bromine and iodine. Alkali metal includes all alkali metalssuch as lithium, sodium and potassium.

In the process of this invention, all compounds having one or moreasymmetric carbon atoms can be produced as racemic mixtures. Theseracemic mixtures which are obtained can be resolved at the appropriatesteps in the process of this invention by methods well known in the artwhereupon subsequent products may be obtained as the correspondingoptically pure enantiomers. On the other hand, the claimed opticallyactive enantiomer or racemates of formula I can be produced dependingupon the optical form of the compound of formula II utilized as astarting material.

In the pictorial representation of the compounds given throughout thisapplication, a thickened taper line ( ) indicates a substituent which isin the beta-orientation (above the plane of the molecule), a dotted line( ) indicates a substituent which is in the alpha-orientation (below theplane of the molecule) and a wavy line ( ) indicates a substituent whichis in either the alpha- or beta-orientation or mixtures of theseisomers. It is to be understood that the pictorial representations ofthe compounds given throughout the specification are set forth forconvenience and are to be construed as inclusive of other formsincluding enantiomers and racemates and are not to be construed aslimited to the particular form shown.

The compounds of formulas I-A and I-B as well as their optical antipodesand racemates are active as anti-secretory agents, bronchodilators,anti-blood platelet aggregators, anti-ulcerogenic agents,anti-hypertensive agents and blood pressure lowering agents.

As also used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, nitro, halo, a lower alkyl or a lower alkoxy substituent,and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl,azulyl, etc., which can be unsubstituted or substituted with one or moreof the aforementioned groups. The preferred aryl groups are thesubstituted and unsubstituted mononuclear aryl groups, particularlyphenyl.

The term "ether protecting group removable by acid catalyzed cleavage"designates any ether which, upon acid catalyzed cleavage yields thehydroxy group. A suitable ether protecting group is, for example, thetetrahydropyranyl ether, or 4-methyl-5,6-dihydro-2H-pyranyl ether.Others are arylmethyl ethers such as benzyl, benzylhydryl, or tritylethers or alpha-lower alkoxy lower alkyl ether, for example,methoxymethyl or allylic ethers, or tri(lower alkyl)silyl ethers such astrimethyl silyl ether or dimethyltert-butyl silyl ethers. The preferredethers which are removed by acid catalyzed cleavage are t-butyl andtetrahydropyranyl and the tri(lower alkyl)silyl ethers, particularlydimethyl-tert-butyl ethers. Acid catalyzed cleavage is carried out bytreatment with a strong organic or inorganic acid. Among the preferredinorganic acids are the mineral acids such as sulfuric acid, hydrohalicacid, etc. Among the preferred organic acids are lower alkanoic acidssuch as acetic acid, para-toluene sulfonic acid, etc. The acid catalyzedcleavage can be carried out in an aqueous medium or in an organicsolvent medium. Where an organic acid is utilized, the organic acid canbe the solvent medium. In the case of t-butyl, an organic acid isgenerally utilized with the acid forming the solvent medium. In the caseof tetrahydropyranyl ethers, the cleavage is generally carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure.

That the prostacyclins of formulas I-A and I-B of this invention areactive as anti-blood platelet aggregating agents can be seen from theadministration of(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester by the following test.

30 Ml. of blood was drawn from the jugular vein of a conscious beagleusing two 15 ml. Vacutainer tubes, with no additive, connected to a 20g. 1 inch multiple sample needle. The blood was immediately transferredto a 50 ml. conical plastic centrifuge tube containing 3 ml. of 3.8%sodium citrate (3.8 grams of sodium citrate crystal, Na₃ C₆ H₅ O₇.2H₂ O,in 100 ml. of distilled water), capped and gently mixed. The citratedblood was centrifuged at 160 g. for 15 minutes at 20° C. The plateletrich plasma (PRP) was carefully withdrawn with a pipette, withoutdisturbing the buffy coat and erythrocyte layers. The PRP was placed in16×125 mm plastic tubes, capped and stored at room temperature 19°-21°C. PRP preparations showing a tinge of redness, indicative of hemolysis,were discarded. The remaining blood, after the removal of PRP, wasrecentrifuged at higher speed, 900 g. for 10 minutes, to yield plateletpoor plasma (PPP). The PRP was used immediately and the aggregationstudy completed within three hours after preparation.

Platelet aggregation was measured with a Payton duel channel aggregationmodule connected to a duel pen recorder for the continuous recording ofthe increase in light transmission due to clumping of platelets. The0-100% transmission scale was set with PRP (0%) and PPP (100%). Thetemperature was set at 37° and the stirring speed at 900 rpm. 0.45 Ml.of PRP was added to a cuvette containing a teflon coated stirring barand prewarmed at 37° in a water bath. 5 μl of various concentrations of(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester, diluted from a stock solution of 5×10⁻⁴ M in DMSO(dimethylsulfoxide) with phosphate buffered saline containing 1 mg/ml.of bovine serum albumin, fraction V, was added and stirred for 1 minute.The inducer of aggregation, arachidonic acid, at a concentration whichwill cause 50-70% aggregation after 5 minutes, was then added in 50 μlof solution. The % inhibition, set forth in the following Table, wascalculated from the ratio of the % aggregation with(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester over that with the vehicle×100.

    ______________________________________                                        Concentration of (5Z,Zβ,9α,11α,                              13E,15R)-7-fluoro-6,9-epoxy-11,15-                                            dihydroxy-16,16-dimethyl-prosta-5,13-                                         dien-1-oic acid methyl ester                                                                        % Inhibition                                            ______________________________________                                        1 × 10.sup.-13 M                                                                              14.2                                                    3 × 10.sup.-13 M                                                                              20.8                                                    1 × 10.sup.-12 M                                                                              71.4                                                    1 × 10.sup.-11 M                                                                              57.8                                                    1 × 10.sup.-10 M                                                                              20.8                                                    ______________________________________                                    

The preparation of phosphate buffered saline and arachidonic acidsolution used above is as follows: Phosphate buffered saline (PBS) wasprepared by adding 1 mM solution of sodium phosphate aqueous buffer, pH7.4 to 0.85% by weight/volume of an aqueous sodium chloride solution.Arachidonic acid solution was prepared as follows: A stock solution of10 mg. per ml. in absolute ETOH was prepared and stored in freezer. Tomake a 10 mM solution, 0.3 ml. of the stock solution was evaporated tonear dryness under nitrogen and redissolved in 0.75 ml. of 0.02 NH₄ OH(freshly prepared) and 0.2 ml. of PBS. Further dilutions of arachidonicacid were made with NH₄ OH and PBS mixture.

The compounds of formulae I-A and I-B or their pharmaceuticallyacceptable salts can be used in a variety of pharmaceuticalpreparations. In these preparations, the new compounds areadministerable in the form of tablets, pills, powders, capsules,injectables, solutions, suppositories, emulsions, dispersions, and inother suitable forms. The pharmaceutical preparations which contain thecompounds of formulae I-A and I-B are conveniently formed by admixingwith a non-toxic pharmaceutical organic carrier or a non-toxicpharmaceutical inorganic carrier. Typical of pharmaceutically acceptablecarriers are, for example, water, gelatin, lactose, starches, magnesiumstearate, talc, vegetable oils, polyalkylene glycols, petroleum jellyand other conventionally employed pharmaceutically acceptable carriers.The pharmaceutical preparations may also contain non-toxic auxiliarysubstances such as emulsifying, preserving and wetting agents and thelike, as for example, sorbitan monolaurate, triethanol amine oleate,polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like.

The daily dose administered for the compounds will, of course, vary withthe particular novel compound employed because of the very potency ofthe compounds, the chosen route of administration and the size of therecipient. The dosage administered is not subject to definite bounds butit will usually be in effective amounts of the pharmacologicallyfunction of the prostacyclin. Representative of a typical method foradministering the prostacyclin compounds of formulae I-A and I-B is byoral administration. By this route, the prostacyclins of formulae I-Aand I-B can be administered at a dosage of 0.1 micrograms to 0.30micrograms per day per kilogram of body weight.

Among the preferred compounds of formulae I-A and I-B are thosecompounds where the 7-fluoro substituent is in the beta configuration.Among the 7-beta fluoro compounds, the following are preferred: ##STR3##When R is lower alkyl in the compound of formulae I-Ai, I-Aii, I-Aiiiand I-Aiiii, R is preferably methyl or ethyl.

The compounds of formulae I-A and I-B are prepared from the compound offormula II via the following intermediates: ##STR4## wherein R, R₁, R₂and R₂ ' are as above, R₁ ' is hydrogen, methyl or OR₄ ; --OR₄ form anether protecting group removable by an acid catalyzed cleavage; R₆ islower alkyl and X is halogen; and R₅ is tri(lower alkyl)silyl.

The compound of formula II is converted to the compound of formula IV byconventional etherification in order to protect any free hydroxy groupsin the compound of formula II. Where R₁ is hydroxy in the compound offormula II, this etherification converts the hydroxy group to theprotected ether in the compound of formula IV. The preferred ethers foruse in this reaction are tetrahydropyranyl and dimethyl-t-butyl silylether. In carrying out this reaction, any conventional method ofetherifying the compound of formula II can be utilized in forming thecompound of formula IV. When a tri(lower alkyl)silyl ether is desired, atri(lower alkyl)chlorosilane is utilized as the etherifying agent in thepresence of an organic base such as imidazol or pyridine. Anyconventional organic amine base can be utilized in carrying out thisreaction.

The compound of formula IV is converted to the compound of formula V byfirst enolizing the compound of formula IV and then treating thecompound of formula IV with a trialkyl halosilane. Enolization isaccomplished by enolizing the compound of formula IV. Any conventionalmethod of enolizing can be utilized to carry out this reaction. Amongthe preferred methods is by treating the compound of formula IV with anon-aqueous alkali metal base. The preferred base for use in thisreaction is lithium diisopropyl amide or sodium hexamethyldisilazane. Incarrying out the reaction utilizing the non-aqueous alkali metal base,temperatures of -70° to -30° are generally preferred. Generally, thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent which is a liquid at the aforementionedtemperatures can be utilized. Among the preferred solvents aretetrahydrofuran. The enolate of the compound of formula IV in the formof its alkali metal salt is converted to the compound of formula V bytreating the compound of formula V with a trialkyl halosilane,preferably trimethylchlorosilane. Generally, this reaction is carriedout at the same temperatures and in the same solvent utilized to formthe enolate.

The compound of formula V is converted to the compound of formula VI bytreating the compound of formula V with a fluorinating agent. Anyconventional fluorinating agent can be utilized in carrying out thisreaction. Among the preferred fluorinating agents are xenon difluoride,fluorine gas, etc. Generally, this reaction is carried out in thepresence of an inert organic solvent. Any conventional inert organicsolvent can be utilized in carrying out this reaction. Among thepreferred solvents are halogenated hydrocarbons such as methylenechloride, carbon tetrachloride, etc. In carrying out this reaction,temperature and pressure are not criitical and this reaction can becarried out at room temperature and atmospheric pressure. While roomtemperature can be utilized, it is preferred to carry out this reactionat low temperatures, i.e. from -10° C. to +10° C.

In converting the compound of formula V to the compound of formula VI,the compound of formula V is produced as a mixture of the followingcompounds: ##STR5##

The compounds of formulae VI-A and VI-B can be separated by conventionalmethods such as chromatography. On the other hand, the compound offormula VI as a mixture of the compounds of formulae VI-A and VI-B canbe utilized throughout the rest of the reaction or, if desired,separated at some later state in the reaction scheme to produce thecompound of formulae I-A or I-B having the desired fluoro orientation atthe 7-position. If the compound of formula VI is separated into thecompound of formula VI-A and VI-B, the same configuration of thefluorine atom is carried out throughout the rest of the reaction.Therefore, if the compounds of formulae I-A or I-B wherein the fluorineatom is at the 7-beta position, the compound of formula VI-A is utilizedin the rest of the reaction scheme producing compounds of the formulaeVII through XVI wherein the fluorine atom set forth in these formulae isin the beta position. If the compounds of I-A and I-B are desiredwherein the fluorine is in the 7-alpha position, then the compound offormula VI-B is utilized in the reaction scheme to produce the compoundsof formulae VII through XVI wherein the fluorine atom shown in theseformulae is in the alpha position.

On the other hand, the compound of formula VI can be utilized withoutseparating it into the compounds of formulae VI-A and VI-B. In thismanner, the compounds of formulae I-A and I-B wherein the fluorine is inboth of the alpha and beta positions is produced via intermediates ofthe formulae VII through XVI having the fluoro group in the sameposition as shown.

In converting the compound of formula II to the compound of formula VI,it is generally preferred to utilize the tri(lower alkyl)silyl ethers asthe hydroxy protecting group. In the conversion of the compounds offormula VI to the compounds of formulae I-A and I-B, it is generallypreferred to protect one or more of the hydroxy groups with atetrahydropyranyl ether. On the other hand, the silyl ethers or anyother conventional ethers can be utilized in the rest of this process.However, in accordance with the preferred embodiment, the silyl ethersof formula VI are hydrolyzed to produce the compound of formula VIIwhich is then reetherified to produce the compound of formula VI whereinthe ether group is tetrahydropyranyl. Any conventional method ofhydrolyzing ethers can be utilized to carry out the conversion of thecompounds of formula VI to the compounds of formula VII and anyconventional method of etherification can be utilized to carry out thereconversion of the compounds of formula VII to the compounds of formulaVI. With tetrahydropyranyl as the protecting group in the compound offormula VI, there is no need to hydrolyze the compound of formula VI tothe compound of formula VII since the compound of formula VIII can beproduced directly from the compound of formula VI.

The compound of formula VII is converted to the compound of formula VIIIby treating the compound of formula VII with a reducing agent. Incarrying out this reaction, any conventional reducing agent which willselectively reduce a keto-group to a hydroxy-group can be utilized.Preferred reducing agents are the hydrides, particularly the aluminumhydrides such as alkali metal aluminum hydride, and the borohydridessuch as alkali metal borohydrides, with diisobutyl aluminum hydridebeing particularly preferred. Also, this reaction can be carried oututilizing di-branched chain lower alkyl)boranes such asbis(3-methyl-2-butyl)borane. In carrying out this reaction, temperatureand pressure are not critical and the reaction can be carried out atroom temperature and atmospheric pressure or at elevated or reducedtemperatures and pressures. Generally, it is preferred to carry out thisreaction at a temperature of from -80° C. to the reflux temperature ofthe reaction mixture. This reduction reaction can be carried out in thepresence of an inert organic solvent. Any conventional inert organicsolvents can be utilized in carrying out this reaction. Among thepreferred solvents are dimethoxy ethylene glycol, and the ethers such astetrahydrofuran, diethyl ether and dioxane.

The compound of formula IX is obtained from the compound of formula VIIIby reacting the compound of formula VIII with phosphonium salts of theformula: ##STR6## wherein R₁₅, R₁₅ ', R₁₅ " is aryl or di(loweralkyl)amino; and Y is halogen

via a conventional Wittig type reaction. Any of the conventionalconditions in Wittig reactions can be utilized in carrying out thisreaction.

The compound of formula IX can be converted to a compound of the formulaX by esterification with diazomethane or a reactive derivative of alower alkanol such as a lower alkyl halide. Any conventional conditionsutilizing in these esterifying reactions can be utilized to form thecompound of formula X from the compound of formula IX.

The compound of formula X is converted to the compound of formula XI bytreating the compound of formula X with a halogenating agent. Among thepreferred halogenating agents are included N-halosuccinimides,particularly N-iodosuccinimide. Generally, this reaction is carried outin the presence of a polar solvent such as acetonitrile and halogenatedhydrocarbons such as methylene chloride, ethylene chloride, etc. Iffact, any conventional polar organic solvent can be utilized. Incarrying out this reaction, temperatures of from 0° to 35° C. can beutilized. Generally, it is preferred to carry out this reaction at roomtemperature.

The compound of formula XI is converted to the compound of formula XIIby ether hydrolysis. Any conventional method of ether hydrolysis can beutilized to carry out this reaction. Generally, it is preferred toutilize mild acid hydrolysis such as aqueous acetic acid.

In the next step, the compound of formula XII is treated with adehydrohalogenating agent to produce the compounds of formulae XIII andXIV in admixture. In carrying out this reaction, any conventionaldehydrohalogenating agent can be utilized. Among the preferreddehydrohalogenating agents are the diazabicycloalkanes or alkknes suchas 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,4-diazabicyclo[2.2.2]octane.Furthermore, any other conventional organic base utilized fordehydrohalogenating can be utilized in carrying out this reaction. Thisreaction produces the compounds of formula XIII and the compounds offormula XIV in admixture. The compounds of formula XIII can be separatedfrom the compounds of formula XIV by any conventional procedure such aschromatography.

The compound of formula XIII is converted to the compound of formula XVand the compound of formula XIV is converted to the compound of formulaXVI by hydrolysis. Any conventional method of ester hydrolysis can beutilized in carrying out these reactions. Among the preferred method ofester hydrolysis is either treating the compound of formula XIII or thecompound of formula XIV with a alkali metal hydroxide. Among thepreferred alkali metal hydroxides for use in this reaction are sodiumand potassium hydroxides.

In the practice of this invention, any pharmaceutically acceptable basicsalts of the compound of formula I-A and I-B where R is hydrogen can beutilized. Among the preferred pharmaceutically acceptable basic saltsare included the alkali metal salts such as lithium, sodium, andpotassium, with sodium being especially preferred. Other salts which arealso preferred are the alkaline earth metal salts such as calcium andmagnesium, amine salts such as the lower alkyl amines, e.g. ethylamineand the hydroxy-substituted lower alkyl amine salts andtris(hydroxymethyl)aminomethane. Also preferred are the ammonium salts.Among the other salts are dibenzylamine, monoalkylamines or dialkylamineand salts with amino acids (i.e. salts with arginine and glycine).

Among the preferred compounds of this invention are compounds of theformula XIII and XV where R₁ and R₂ are both hydrogen.

The following Examples are illustrative but not limitative of theinvention. In the Examples, the ether utilized was diethyl ether. Alltemperatures are in degrees Centigrade. The petroleum ether utilized inthe Examples had a boiling point of from 35° to 60° C. In the Examples,"h" indicates hours.

EXAMPLE 1[3aR-[3aα,4α(1E,3R*),5β,6aα]]-Hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one

502.2 mg (1.69 mmol) of[3aR-[3aα,4α(1E,3R*),5β,6aα]]-hexahydro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one,was dissolved in 15 mL of dimethylformamide (reagent grade, dried over3A molecular sieves) under a positive argon pressure. 1.045 g (6.93mmol=4.09 eq.) of t-butyldimethylchlorosilane (dist. before use) and587.6 mg (8.63 mmol=5.09 eq.) of imidazole (reagent grade) were added.The resulting mixture was stirred at room temperature for 18 h, pouredinto 60 ml ice cold 0.5N aqueous HCl and extracted three times with 60ml of diethylether. The extracts were washed with 60 ml of a mixture ofsat. aqueous NaHCO₃ /H₂ O/brine=1:1:2 followed by washing with 60 mlbrine. The extracts were combined, dried over MgSO₄ and concentrated atreduced pressure. 1.25 g of a white semi-solid remained. The crudeproduct was chromatographed on a 75 g silica gel column with 10% byvolume ether/90% by volume petroleum ether (first 1 lt) followed by 20%by volume ether/80% by volume petroleum ether. 857.1 mg (1.63 mmol,96.4%) of[3aR-[3aα,4α(1E,3R*),5β,6aα]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-oneas a white amorphous solid was obtained; mp 67°-68°.

EXAMPLE 2[3aR-[3aα,4α(1E,3R*),5β,6aα]]-4,5,6,6a-Tetrahydro-5-[[1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2-(trimethylsilyl)-oxy-3aH-cyclopenta[b]furan

570 μl (4.07 mmol) of diisopropylamine (dist. from CaH₂) was dissolvedin 15 ml of tetrahydrofuran (freshyl dist. from LAH). The mixture wascooled to +3° C. under a positive argon pressure. 2.5 ml (3.75 mmol) of1.5N n-butyllithium in hexane was added dropwise at +3° C. Afterstirring at +3° C. for 5 min, the mixture was cooled to -40° C. with adry ice/acetone bath. 1.757 g (3.35 mmol) of[3aR-[3aα,4α(1E,3R*),5β,6aα]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)-dimethylsilyl]-oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-onedissolved in 6 ml THF was added dropwise to the lithium diisopropylamidesolution at -40° C. After stirring at -40° C. for an additional 5 min.570 μl (4.49 mmol) of trimethylchlorosilane (dist.) was added rapidly.Two min after the addition, the cooling bath was removed and the mixturewas allowed to warm to +15° C. over a 20 min period. The solvent wasremoved under vacuum (ca 0.2 MMHG) at or below room temperature and theresidue was dried at high vacuum for 15 min. 10 mL of ether (freshlyfiltered through aluminum oxide, activity I) was added under argon andthe mixture was filtered through a sintered glass funnel. The whiteresidue was washed three times with 3 mL of ether. The slightly yellowfiltrate was concentrated under vacuum and the oily residue was dried athigh vacuum (room temperature) for 1 h. producing[3aR-[3aα,4α(1E,3R*),5β,6aα]]-4,5,6,6a-tetrahydro-5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2-(trimethylsilyl)oxy-3aH-cyclopenta[b]furan.

EXAMPLE 3[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-Hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta-[b]furan-2-one

The compound[3aR-[3aα,4α(1E,3R*),5β,6aα]]-4,5,6,6a-tetrahydro-5-[[1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2-(trimethylsilyl)oxy-3aH-cyclopenta[b]furanwas dissolved in 15 mL of methylene chloride (freshly filtered throughaluminum oxide, activity I) under argon. The mixture was cooled to +2°C. with an ice/water bath. 680 mg (6.8 mmol) of potassium bicarbonate(dried at high vacuum at 100° over P₂ O₅ for 3 h) followed by 632.9 mg(3.73 mmol) of xenon difluoride were added under stirring. An immediatereaction ensued as judged by the vigorous gas evolution in the first 30sec. after the addition of XeF₂. The mixture was stirred at +2° C. for20 min, poured into 150 mL of ice cold water and extracted three timeswith 150 ml of methylene chloride. The extracts were washed twice with150 ml of brine, combined, dried over MgSO₄ and concentrated at reducedpressure. The residue was dried at high vacuum for 18 h leaving 1.92 gof a yellowish oil.

The crude product was chromatographed on 200 g of silica gel (230-400mesh) using the flash chromatography technique. 5% by volume ethylacetate/95% by volume petroleum ether (1 lt) followed by 10% ethylacetate/petroleum ether were used as eluting solvents. The followingproducts were obtained in order of elution: 1.06 g (1.95 mmol) 58% of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]-oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one;white needles formed on standing, m.p. 49°-51°; 165.2 mg (0.315 mmol)9.4% of[3aR-[3aα,4α(1E,3R*),5β,6aα]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one, starting material; and 98.9 mg (0.182 mmol) 5.4% of3R-[3β,3aα,4α(1E,3R*),5β,6aα]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]-oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one;amorphous white solid; m.p. 83°-85°.

EXAMPLE 4[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-Hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one

1.597 g (2.94 mmol) of the fluoro lactone[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-onewas dissolved in 60 ml of acetic acid (reagent grade) and the mixturewas warmed to 55° C. under a positive argon pressure. 6 ml of water wasadded with stirring at 55° C. After 7 h, an additional 4 ml of water wasadded and stirring at 55° C. was continued for 64 h (71 h total). Aftercooling to room temperature, the solvent was removed under vacuum (ca.0.2 Torr) at 25°-30° C. The oily residue was dried at high vacuum for 2h at room temperature, followed by chromatography on 200 g of silica gel(230-400 mesh) using solvent mixtures ranging from ethylacetate/petroleum ether 1:1 parts by volume to pure ethyl acetate forelution.

351.2 mg of partially hydrolyzed material containing large amounts ofimpurities and 571.5 mg (1.82 mmole, 62%) of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one(oil) were obtained. Resubjecting the 351.2 mg of partially hydrolyzedmaterial to similar reaction conditions (HOAc, H₂ 0) for 42 h resultedin the formation of 39.6 mg (0.126 mmole) 4.3% of additional[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-one.Total yield of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-onewas 611.1 mg (1.94 mmol) 66%, oil, clear.

EXAMPLE 5[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-Hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-one

571.5 mg (1.82 mmol) of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-hydroxy-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2H-cyclopenta[b]furan-2-onewas dissolved in 20 ml of methylene chloride (freshly filtered throughaluminum oxide, activity I) under a positive argon pressure. 2.0 ml(21.9 mmol) of dihydropyran (freshly dist. from sodium) was added understirring followed by a crystal of p-toluenesulfonic acid monohydrate(9.7 mg; 0.05 mmol). The mixture was stirred at room temperature for 30min, poured into 50 ml of sat. aqueous sodium bicarbonate and extractedthree times with 30 ml of methylene chloride. The extracts were washedtwice with 50 ml of brine, combined, dried over MgSO₄ and concentratedat reduced pressure. The crude product (1.14 g, oil) was chromatographedon a 100 g silica gel column with ether/petroleum ether(1:1) yielding797 mg (1.65 mmol) 91% of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-oneas a clear oil (mixture of THP-diastereomers). [α]_(D) ²⁵ -32.46° inCHCl₃, c=0.8780.

EXAMPLE 6[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-Hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-ol

After dissolving 729.2 mg (1.51 mmol) of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-onein 10 ml of toluene (dist. from CaH₂) under argon, the mixture wascooled to approx. -70° C. with a dry ice/acetone bath. 1.25 ml (1.75mmol) of a 1.4M solution of diisobutylaluminum hydride in hexane wasadded dropwise at -70° C. The mixture was stirred at -70° C. for 20 min.3 ml of a saturated aqueous ammonium chloride solution was addeddropwise at -70° C. and the resulting mixture was transferred with 20 mlof water and 50 ml of ethyl acetate into a separatory funnel. Shakingcaused a very thick suspension to form, which was filtered throughcelite. The residue was washed thoroughly with 100 ml of ethyl acetate.The filtrate was again transferred into a separatory funnel and washedonce with 60 ml of brine/water (1:1 parts by volume) and once with 100ml brine. The aqueous washings were reextracted once with 80 ml of ethylacetate. The organic extracts were combined, dried over MgSO₄ andconcentrated at reduced pressure. Flash chromatography on 200 g ofsilica gel (230-400 mesh) of the crude product (806 mg; oil) with ethylacetate/petroleum ether (4:6) gave 661.5 mg (1.36 mmol) 90% of[3S-[3α,3aα,4α-(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-olas an amorphous solid, m.p. 58°-66° C.; [α]_(D) ²⁵ =12.83° in CHCl₃,c=1.0290.

EXAMPLE 7(5Z,7R,9α,11α,13E,15R)-7-Fluoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oicacid methyl ester

1.54 g (3.47 mmol) of (4-carboxybutyl)triphenylphosphonium bromide(dried at high vacuum at 100° over P₂ O₅ for 2 h) and 1.275 g (6.95mmol) of sodium hexamethyldisilazane (dist.) were placed into a threeneck flask under argon. 20 ml of tetrahydrofuran (freshly dist. fromLAH) and 1.25 mL (7.18 mmol) of hexamethylphosphoramide (dist.) wereadded. This mixture was stirred at room temperature for 11/2 h. To theorange red suspension was added dropwise a solution of 560.5 mg (1.16mmol) of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]-hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-olin 4 ml of tetrahydrofuran. The resulting yellow-orange mixture wasstirred at room temperature for 4 h. The reaction was quenched by thedropwise addition of glacial acedic acid (faint yellow color). Most ofthe solvent was evaporated under high vacuum at or below roomtemperature. The residue was transferred with 100 mL of ether and 100 mlof water into a separatory funnel. The aqueous phase was acidified to pH3 with 13 mL of 1N HCl. After shaking and separation of the two phases,the aqueous phase was reextracted twice with 70 mL of ether. The organicextracts were washed twice with 70 ml of brine, combined and dried overMgSO₄. After removal of the solvent, the oily residue was dried at highvacuum for 11/2 h, leaving 1.45 g of an oil. This crude acid wasdissolved in 10 mL of methylene chloride (freshly filtered throughaluminum oxide, activity I) and esterified at room temperature by theaddition of 15 mL (3.75 mmol) of a 0.25N solution of diazomethane inether. After removal of the solvent at aspirator pressure, the remainingoil (1.27 g) was dissolved in 10 mL of tetrahydrofuran and 2.8 mL (2.8mmol) of a 1.0M solution of tetra-n-butylammonium fluoride intetrahydrofuran. was added. The mixture was stirred at room temperaturefor 15 min, poured into 100 ml of a half concentrated aqueous ammoniumchloride solution and extracted three times with 100 ml of ether. Theextracts were washed twice with 70 ml of brine, combined, dried overMgSO₄ and concentrated at reduced pressure. 1.24 g of a yellow oil wasobtained. Chromatography on 100 g of silica gel with ethylacetate/petroleum ether (3:7) (700 ml) followed by ethylacetate/petroleum ether (1:1 parts by volume) gave 20.8 mg (3.7%) of[3S-[3α,3aα,4α(1E,3R*),5β,6aα]]-hexahydro-3-fluoro-5[(tetrahydro-2H-pyran-2-yl)oxy]-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4,4-dimethyl-1-octenyl]-2H-cyclopenta[b]furan-2-ol(starting material) and 496.3 mg (0.85 mmol) 73% of(5Z,7R,9α,11α,13E,15R)-7-fluoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oicacid methylester (oil), as a mixture of diastereomers; [α]_(D).sup. 25=+2.74° in CHCl₃, c=0.9116.

EXAMPLE 8(7β,9α,11α,13E,15R)-16,16-Dimethyl-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

246.9 mg (0.424 mmol) of(5Z,7R,9α,11α,13E,15R)-7-fluoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oicacid methyl ester was dissolved in 10 mL of acetonitrile (dried over 3Amolecular sieves) under a positive argon pressure. 476.9 mg (2.12 mmol,5 eq.) of N-iodo succinimide was added under stirring, the flask wasflushed with argon, closed with a stopper and wrapped in aluminum foilto protect the reaction mixture from light. The mixture was stirred atroom temperature for 27 h, poured into 100 mL of a 10% weight by volumesolution of sodium thiosulfate in water and extracted three times with100 mL of methylene chloride. The organic extracts were washed twicewith 100 ml of brine, combined, dried over MgSO₄ and concentrated ataspirator pressure. 285.9 mg of an oily residue was obtained.Chromatography on 75 g of silica gel with ether/petroleum ether (1:1parts by volume) gave 186.7 mg (0.263 mmol) 62% of(7β,9α,11α,13E,15R)-16,16-dimethyl-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester (oil) as a mixture of diastereomers.

EXAMPLE 9(7β,9α,11α,13E,15R)-16,16-Dimethyl-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

10.6 mg (15 μmol) of(7β,9α,11α,13E,15R)-16,16-dimethyl-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester was dissolved in a mixture of 3 mL of tetrahydrofuran(freshyl dist. from LAH), 6 mL of glacial acetic acid and 3 mL of waterunder a positive argon pressure. The mixture was heated in an oil bathat 40° C. and stirred for 19 h. After cooling to room temperature, thesolvent was removed at high vacuum at 25°. 2 mL of toluene was added andthe solvent was again removed at high vacuum at 25°. The oily residue(11.2 mg) was chromatographed on a thin layer silica gel plate withether giving 6.3 mg (11.65 mol, 78%) of(7β,9α,11α,13E,15R)-16,16-dimethyl-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester (oil) as a mixture of isomers.

EXAMPLE 10(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester

6.3 mg (11.66 μmol) of(7β,9α,11α,13E,15R)-16,16-dimethyl-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester (mixture of isomers) was dissolved in 2.0 mL oftoluene (dist. from CaHD₂) under a positive argon pressure. 20 μl (134μmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (dist. from CaH₂) was added.With stirring, the mixture was slowly heated to 90° C. (over 90 min) andkept at 90° C. for 22 h. After cooling to room temperature, the mixturewas poured into 75 ml of half saturated brine and extracted three timeswith 20 mL of ether. The extracts were washed once with 20 mL of brine,combined, dried over MgSO₄ and concentrated at aspirator pressure. Theremaining oil was dried at high vacuum for 3 h and the 6.2 mg ofresidual oil was chromatographed on a thin layer silica gel plate withethyl acetate. Two products were isolated: 3.0 mg (7.27 μmol) 62% of(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester (oil) and 1.1 mg (2.66 μmol) 23% of(4E,6α,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-4,13-dien-1-oicacid methyl ester (oil).

EXAMPLE 11(5Z,7β,9α,11α,13E,15R)-7-Fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid sodium salt

3.0 mg (7.27 μmole) of(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid methyl ester was dissolved in 0.5 ml methanol and 0.5 ml waterunder argon. 73 μl (7.3 μmole=1 eq) 0.1N sodium hydroxide was added andthe mixture was stirred at room temperature for 2 hr. The methanol wasremoved at reduced pressure and the remaining aqueous solution waslyophilized to give(5Z,7β,9α,11α,13E,15R)-7-fluoro-6,9-epoxy-11,15-dihydroxy-16,16-dimethyl-prosta-5,13-dien-1-oicacid sodium salt as a white powder; m.p. 48°-51° C.

EXAMPLE 12[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-4-[[[(3-(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-fluoro-1-octenyl]-2-H-cyclopenta[b]furan-2-one

By the procedure of Example1[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-4-[4-fluoro-3-hydroxy-1-octenyl)-2H-cyclopenta[b]furan-2-onewas converted to[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl)-2H-cyclopenta[b]furan-2-one.

EXAMPLE 13[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-3-fluoro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one

By the procedure of Examples 2 and 3,[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexa-hydro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-onewas converted to[3aR-3aα,4α(1E,3R*,4R*)6α]]-hexahydro-3-fluoro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-furan-2-one.

EXAMPLE 14[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-3-fluoro-4-[(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one

By the procedure of Example 4[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-[[[3-(1,1-dimethylethyl)dimethylsilyl]oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]-furan-2-onewas converted to[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one.

EXAMPLE 15[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-on

By the procedure of Example 5[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-onewas converted to[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one.

EXAMPLE 16[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-Hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 6[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-onewas converted to[3aR-[3aα,4α(1E,3R*,4R*)6a]]-hexahydro-3-fluoro-4-[3-[(tetrahydro-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 17(5Z,9α,13E,15R,16R)-7,16-Difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-5,13-dien-1-oicacid methyl ester

By the procedure of Example 7[3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4[3-[(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-olwas converted to(5Z,9α,13E,15R,16R)-7,16-difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-prosta-5,13-dien-1-oicacid methyl ester.

EXAMPLE 18(9α,13E,15R,16R)-7,16-Difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-5-iodoprosta-13-en-1-oicacid methyl ester

By the procedure of Example 8,(5Z,9α,13E,15R,16R)-7,16-difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-prosta-5,13-dien-1-oicacid methyl ester was converted to(9α,13E,15R,16R)-7,16-difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-5-iodoprosta-13-en-1-oicacid methyl ester.

EXAMPLE 19(9α,13E,15R,16R)-7,16-Difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oicacid methyl ester

By the procedure of Example 9,(9α,13E,15R,16R)-7,16-difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-6,9-epoxy-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to(9α,13E,15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oicacid methyl ester.

EXAMPLE 20(5Z,9α,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oicacid methyl ester

By the procedure of Example 10(9α,13E,15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to(5Z,9α,13E,15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy-prosta-5,13-dien-1-oicacid methyl ester.

EXAMPLE 21(5Z,9α,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oicacid sodium salt

By the procedure of Example 11,(5Z,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oicacid methyl ester was converted to(5Z,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-5,13-dien-1-oicacid sodium salt.

EXAMPLE 22(4E,9α,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid methyl ester

By the procedure of Example 10,(9α,13E,15R,16R)-7,16-difluoro-15-hydroxy-6,9-epoxy-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to(4E,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid methyl ester.

EXAMPLE 23

By the procedure of Example 11,(4E,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid methyl ester was converted to the sodium salt of(4E,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid.

EXAMPLE 24

A tablet was found containing:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        (5Z,9α,13E,15R,16R)-7,16-Difluoro-6,9-epoxy-15-                                                   25     mg.                                          hydroxy-prosta-5,13-dien-1-oic acid sodium salt                               Dicalcium phosphate dihydrate, unmilled                                                                 175    mg.                                          Corn Starch               24     mg.                                          Magnesium stearate        1      mg.                                          Total Weight              225    mg.                                          ______________________________________                                    

The active ingredient and corn starch were mixed together and passedthrough a #00 screen in Model "J" Fitzmill with hammers forward. Thispremix was then mixed with dicalcium phosphate and one-half of themagnesium stearate, passed through a #1Z screen in Model "J" Fitzmillwith kniver forward, and slugged. The slugs were passed through a #2Aplate in a Model "D" Fitzmill at slow speed with knives forward and theremaining magnesium stearate was added. This mixture was mixed andcompressed.

EXAMPLE 25

A tablet was formulated in the same manner as in Example 24 except that(4E,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid methyl ester was the active ingredient.

EXAMPLE 26

A capsule was prepared containing the following ingredients:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        (5Z,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-                                                   200    mg.                                          hydroxy-prosta-5,13-dien-1-oic acid sodium salt                               Dicalcium phosphate dihydrate, unmilled                                                                 235    mg.                                          Corn Starch               70     mg.                                          FD&C Yellow #5 - Aluminum Lake 25%                                                                      2      mg.                                          Durkee Duratex*           25     mg.                                          Calcium Stearate          3      mg.                                                                    535    mg.                                          ______________________________________                                         *Hydrogenated cotton seed oil (fully saturated)                          

All of the above ingredients were mixed until thoroughly blended in asuitable size container. The powder was filled in to #2, two-piece,hard-shell gelatin capsules to an approximately fill weight of 350 mgusing a capsulating machine.

EXAMPLE 27

A capsule was prepared by the procedure of example 24 except that(4E,9α,13E,15R,16R)-7,16-difluoro-6,9-epoxy-15-hydroxy-prosta-4,13-dien-1-oicacid methyl ester was the active ingredient.

EXAMPLE 283,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-one

To a solution of diisopropylamine in 9 ml of THF (tetrahydrofuran)cooled to 0°-5° C., was added dropwise 1.32 ml of a 2.2M solution ofn-butyl lithium in hexane. The mixture was stirred for 5 min. and cooledto -40° C. with a dry ice acetone bath. A solution of 1 g of3,3aR,4,5,6,6aS-hexahydro-4R[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-onein 6 ml of THF (tetrahydrofuran) was added dropwise over 1 minute andstirred at -45° C. for 5 min. Trimethylchlorsilane (4.26 ml) was thenadded and the mixture stirred at -40° C. for 5 min. The mixture was thenallowed to warm to 0° C. and the solvent removed under high vacuum.Diethyl ether (5 ml) was added to the residue and the cold mixturefiltered through a sintered glass funnel. The solvent was then removedunder high vacuum (ice bath) and the residue dissolved in 10 ml of CH₂Cl₂. To the solution at 0° C. was then added 530 mg of potassiumbicarbonate followed by 429 mg of xenon difluoride. After the gasevolution ceased, the mixture was stirred for an additional 15 min. anddiluted with 50 ml of CH₂ Cl₂. The solution was then washed with 50 mlof H₂ O+2×50 ml of brine. The aqueous phase was separated and backwashed with 50 ml of CH₂ Cl₂. The organic layers were combined, dried(MgSO₄) and the solvents removed under reduced pressure to give 0.95 gof crude product. Chromatography on 50 g of silica gel afforded 300 mgof3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-tans-octenyl]-5R-methyl-2H-cyclopenta[b]furan.

EXAMPLE 293,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 6,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[4,4-dimethyl-3R-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-onewas converted to3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R[4,4-dimethyl-3R-(2-tetrahydropyranyloxy[-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 3011R,16,16-Trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoicacid methyl ester

By the procedure of Example 7,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R[4,4-dimethyl-3R-(2-tetrahydro-pyranyloxy)-1-trans-octenyl]-5R-methyl-2H-cyclopenta[b]furan-2-olwas converted to11R,16,16-trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoicacid methyl ester.

EXAMPLE 31(9S,11R,13E,15R)-11,16,16-Trimethyl-15-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

By the procedure of Example 8,11R,16,16-trimethyl-7-fluoro-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoicacid methyl ester was converted to(9S,11R,13E,15R)-11,16,16-trimethyl-15(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester.

EXAMPLE 32(9S,11R,13E,15R)-11,16,16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

By the procedure of Example 9,(9S,11R,13E,15R)-11,16,16-trimethyl-15-(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to(9S,11R,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester.

EXAMPLE 33(5Z,9S,11R,13E,15R)-11,16,16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester and(4E,9S,11R,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oicacid methyl ester

By the procedure of Example 10,(9S,11R,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to a mixture which was separated by theprocedure of Example 10 to(5Z,9S,11R,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester.

Calc. for C₂₄ H₃₉ FO₄ C: 70.21; H: 9.57; F: 4.63; Found C: 70.00; H:9.44; F: 4.49.

ir 3615, 1733, 1694 cm⁻¹ ; ultraviolet λmax 213 nm (ε=12000) and(4E,9S,11R,15R)-11,16-16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oicacid methyl ester,

Calc. C: 70.21; H: 9.57; F: 4.63; Found C: 70.19; H: 9.52; F: 4.85.

ir 3615, 1735, 1670 cm⁻¹.

EXAMPLE 34(5Z,9S,11R,13E,15R)-11,16,16-Trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid sodium salt

By the procedure of Example 11,(5Z,9S,11R,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester was converted to(5Z,9S,11R,13E,15R)-11,16,16-trimethyl-15-hydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid sodium salt.

EXAMPLE 353,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one

By the procedure of Example 28,3,3aR,4,5,6,6aS-hexahydro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-onewas converted to3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one.

EXAMPLE 363,3aS,4,5,6,6aS-Hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-one

By the procedure of Example 6,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-onewas converted to3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 3711R,15S-Di(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoicacid methyl ester

By the procedure of Example 7,3,3aS,4,5,6,6aS-hexahydro-3-fluoro-4R-[3S-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5R-(2-tetrahydropyranyloxy)-2H-cyclopenta[b]furan-2-olwas converted to11R,15S-di(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxyprosta-cis-5-trans-13-dienoicacid methyl ester.

EXAMPLE 38(9S,11R,13E,15S)-11,15-Di(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

By the procedure of Example 8,11R,15R-di(2-tetrahydropyranyloxy)-7-fluoro-9S-hydroxy-prosta-cis-5-trans-13-dienoicacid methyl ester was converted to(9S,11R,13E,15S)-11,15-di(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester.

EXAMPLE 39(9S,11R,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester

By the procedure of Example 9,(9S,11R,13E,15S)-11,15-di(2-tetrahydropyranyloxy)-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to(9S,11R,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester.

EXAMPLE 40(5Z,9S,11R,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester and(4E,9S,11R,15R)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oic acidmethyl ester

By the procedure of Example 10(9S,11R,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-5-iodo-prosta-13-en-1-oicacid methyl ester was converted to a mixture which was separated inaccordance with the procedure of Example 10 to produce(5Z,9S,11R,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester and(4E,9S,11R,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-4,13-dien-1-oic acidmethyl ester.

EXAMPLE 41(5Z,9S,11R,13E,15S)-11,15-Dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid sodium salt

By the procedure of Example 11,(5Z,9S,11R,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid methyl ester was converted to(5Z,9S,11R,13E,15S)-11,15-dihydroxy-6,9-epoxy-7-fluoro-prosta-5,13-dien-1-oicacid sodium salt.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R₆ is hydrogen or lower alkyl, R₁ ' is methyl, hydrogen or --OR₅ ; R₂ is hydrogen, methyl or fluoro, R₂ ' is fluoro, hydrogen, trifluoromethyl or methyl; --OR₅ forms a hydrolyzable ether protecting group; with the proviso that when R₂ ' is trifluoromethyl, R₂ is hydrogen or methyl.
 2. The compound of claim 20 wherein R₁ ' is --OR₅.
 3. The compound of claim 21 wherein said compound is (5Z,7R,9α,11α,13E,15R)-7-fluoro-11,15-di[(tetrahydro-2H-pyran-2-yl)oxy]-16,16-dimethyl-9-hydroxy-prosta-5,13-dien-1-oic acid methyl ester.
 4. The compound of claim 20 wherein R₁ ' is hydrogen.
 5. The compound of claim 23 wherein R₁ is (5Z,9α,13E,15R,16R)-7,16-difluoro-15[(tetrahydro-2H-pyran-2-yl)oxy]-9-hydroxy-5,13-dien-1-oic acid methyl ester. 